Apoptosis is a form of programmed cell death. It results from the activation of a cascade of genes, makes the self-destruction of superfluous cells possible and plays a decisive role during embryonic development. Also, in the modeling of the cerebral structures over the course of embryonic and fetal development apoptosis plays an important role. As has been said, these development processes are based on the differentiation and subsequent migration of the embryonic neurons to specific brain regions. There, then, a contest occurs between the nerve cells in establishing synaptic connections. If the formation of such synaptic contacts fails to occur, the neurons are subject to apoptosis. This phenomenon is also involved in the development of numerous other organs. Thus, namely, the transfiguration of the hand plate in the morphogenesis of land vertebrate fingers and the involution of Wolff’s and Müller’s course in the development of the genitourinary tract are based on this mechanism.
The first morphologic signs of apoptosis consist in a cell contraction, nuclear fragmentation, a fragmentation of the DNA and a condensation of the cytoplasma. In addition, the formation of membrane vesicles ("blebs") can be observed. In the end, cell death through apoptosis leads to a fragmentation of the whole cell so that apoptotic bodies arise that (in contrast to necrotic cells) exhibit an intact membrane and contain organelles, nucleus fragments and a condensed cytoplasma in their interiors. These cell fragments are phagocytized either from specific scavenger cells or by neighbor cells without an inflammatory reaction.
Apoptosis differs from necrosis, a form of the cell death in which all cell organelles are destroyed very quickly. The absence of regulatory mechanisms for steering the cell's interior pressure leads to membrane ruptures and to an outflow of the cell contents into the surrounding tissue. This then results in a triggering of inflammatory reactions.
In a developing brain nerve cells compete with one another in making synaptic contacts. Those nerve cells that enter into no contacts with other cells fall victim to apoptosis.
With this, apoptosis also plays a central role in the context of neurodegenerative diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis as well as in acute pathological mutations (cerebral ischemia, traumatic brain injury).
Apoptosis versus Necrosis
- Active process accompanied with the expression specific genes (the expression of the corresponding genes can also be inhibited).
- Condensation of chromatin and cytoplasma with non-random fragmentation of the DNA.
- Organelles and cell membrane remain intact (aptotic bodies).
- Absence of inflammatory processes; cell remains are phagocytized by neighbor cells.
- The phagocytotically active cells secrete inflammation-inhibiting cytokine.
- Passive process
- Flocculation of the chromatins with random fragmentation of the DNA.
- Destruction of the cell membrane, lysis of the cell organelles.
- Release of the cell contents into the intercellular space.
- Subsequent inflammatory reaction.
The most important triggers of apoptosis
Apoptosis can be triggered by various factors. Among these are:
- The activation of apoptogenetic membrane receptors (especially by TNF-α or by cell-death-specific ligands like Fas)
- The activation of nucleus-bound receptors (glucocorticoid)
- The effects of a wide variety of stress factors (viral infections, hypoxia, ionizing radiation with DNA mutations, etc.)
- The suppression of a survival signal by the deprivation of growth factors (NGF, BDNF, CNTF)
During embryonic development the suppression of a survival signal seems to be the most frequent trigger of apoptosis.
Already in the fifties Hamburger and Levi-Montalcini have shown that the development of the embryonic cerebral centers is subject to the influence of peripheral neurotrophic factors that are secreted by the target cells. In a 1958 article Hamburger showed that the amputation of an extremity stump incurs the cell death of a considerable number of motor neurons on the contralateral side of the spinal cord. Levi Montalcini discovered the Nerve Growth Factor as a survival factor for certain nerve cells.
Nevertheless, numerous mechanisms in the steering of apoptosis by neurotrophic factors still lie in darkness.